Amyotrophic lateral sclerosis (ALS) is a debilitating neurological disorder associated with diminished motor function resulting in muscle wasting and death in 3-5 years, often as the result of respiratory failure. ALS is thought to be caused by a combination of both environmental and genetic risk factors, with ca. 15% of the disease prevalence clearly associated with inherited mutations (familial ALS, fALS) such as those associated with superoxide dismutase (SOD1) and on chromosome 9 (GGGGCC repeats). ALS imparts a great deal of suffering upon both patients and caregivers, and places a large burden upon the health care system in that as many as 10 health care professionals are required to provide patient care during the course of the disease. It is estimated that the lifetime risk of developing ALS is 1:1000, and that 15-20 new patients are diagnosed with the disease every day in the U.S. ALS is an orphan indication consisting at any time of 30,000-40,000 individuals in the U.S. and >300,000 worldwide. The financial burden for the treatment of ALS ranges from ca. $3,100 to $5,800 per year, with late stage ventilation treatment costing from ca. $160,000 for in-home to $430,000 per year for institutional treatment. The mean time spent on ventilation in the terminal stage of the disease is three years rendering this a cost-prohibitive option not available to many patients. The only approved treatment for ALS is Rilutek® (riluzole, 1) which increases lifespan by only 2-3 months after 1.5 years of treatment, and is effective at delaying tracheostomy upon bulbar patients. There is a clear unmet medical need for improved treatment options for patients who suffer from ALS.

Riluzole (Rilutek®) the only FDA-approved treatment for amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease). Riluzole has a mild side-effect profile among ALS patients. However, the therapeutic utility of riluzole itself in ALS is constrained by rapid first-pass metabolism in the liver and an exceptionally high level of patient-to-patient variability in the extent of the Cyp1A2-mediated oxidative metabolism that is observed. Pro-drugs of riluzole that avoid first pass, hepatic metabolism and are cleaved in plasma to deliver riluzole will provide more predictable pharmacokinetic properties and metabolic profiles for the parent compound, leading to an improved therapeutic effect.
Riluzole is also clinically relevant in additional disease states. These include, but are not limited to, bipolar disorder, treatment resistant and major depression, obsessive-compulsive disorder, spinal muscular atrophy, radiation therapy, multiple sclerosis, chronic cerebellar ataxia, cervical spondylotic myelopathy, spinal cord injury, hereditary cerebellar ataxia, Tourette syndrome, autism spectrum disorder, schizophrenia, fragile X syndrome, Parkinson's Disease, and Huntington's disease. Pro-drugs of riluzole will provide more predictable pharmacokinetic properties and metabolic profiles for the parent compound, leading to an improved therapeutic effect in each of the aforementioned disease states.
There is a long felt need for new treatments for ALS that are both disease-modifying and effective in treating ALS patients. The present invention addresses the need to identify new treatments for ALS by indentifying novel pro-drugs of riluzole which possess enhanced stability to hepatic metabolism and are delivered into systemic circulation by oral administration. The riluzole pro-drugs are cleaved to release riluzole in the plasma via either an enzymatic or general biophysical release process.
There is also a long felt need for new treatments for disease states in which riluzole is clinically relevant including, but are not limited to, bipolar disorder, treatment resistant and major depression, obsessive-compulsive disorder, spinal muscular atrophy, radiation therapy, multiple sclerosis, chronic cerebellar ataxia, cervical spondylotic myelopathy, spinal cord injury, hereditary cerebellar ataxia, Tourette syndrome, autism spectrum disorder, schizophrenia, fragile X syndrome, Parkinson's Disease, and Huntington's disease. The present invention addresses the need to identify treatments for disease states in which riluzole is clinically relevant by indentifying novel pro-drugs of riluzole which possess enhanced stability to hepatic metabolism and are delivered into systemic circulation by oral administration. The riluzole pro-drugs are cleaved to release riluzole in the plasma via either an enzymatic or general biophysical release process.